We are looking for motivated graduate students and postdocs. Email: [email protected].

“Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows tracings of her workings apart from the beaten paths; nor is there any better way to advance the proper practice of medicine than to give our minds to the discovery of the usual law of nature, by careful investigation of cases of rarer forms of disease”  - William Harvey

The research in our laboratory is broadly focused on hematopoietic growth control, genetic mechanisms underlying leukemogenesis, aberrant Ras signaling, mouse cancer modeling, and molecular therapeutics. In accordance with Harvey’s adage, our studies of children with inherited predispositions to myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), and acute myeloid leukemia (AML) uncovered genes, proteins, and pathways that play central roles in development and cancer. We are using genetics/genomics, biochemistry, cell biology, and mouse models to characterize the underlying molecular mechanisms and to address key therapeutic questions.

Neurofibromatosis type 1 (NF1) is the founding member of the “Rasopathies” – a group of development disorders caused by germline mutations in genes involved in Ras signaling. The NF1 gene, which encodes a GTPase activating protein that negatively regulates Ras output, functions as a tumor suppressor in juvenile myelomonocytic leukemia (JMML) and other cancers. This observation and subsequent research showing that JMML is fundamentally a disease of hyperactive Ras led to the development of genetically accurate mouse models that have informed clinical translation. Other work in our lab uncovered novel germline KRAS mutations as a cause of Rasopathy disorders, which we characterized genetically and functionally. Recent and ongoing projects in the lab make use of primary AMLs and acute lymphoblastic leukemias (ALLs)  generated in Nf1, Nras, and Kras mutant mice as a forward and unbiased system for investigating response and resistance to targeted and conventional anti-cancer agents.

Myelodysplasia and Leukemia Syndrome with Monosomy 7 (MLSM7; OMIM 252270) is a rare familial cancer syndrome caused by gain-of-function SAMD9 and SAMD9L mutations that are lost in the monosomy 7 bone marrows of affected patients due to a novel “adaptation by aneuploidy” mechanism. More broadly, monosomy 7 and del(7q) are frequently detected in patients with MDS, MPN, and AML. We have harnessed chromosome engineering technology to create large segmental deletions in the mouse corresponding to the frequent losses of human chromosome 7q22 seen in human leukemia cells. Ongoing work includes characterizing the hematopoietic stem and progenitor cell compartments of these mice and interrogating how these segmental deletions cooperate with SAMD9/9L haploinsufficiency in leukemogenesis.

Recent post-doctoral trainees have launched successful careers at leading academic institutions, biotechnology companies in the San Francisco Bay Area, and in government. Interested individuals are welcome to contact current or past members of the lab directly, and are encouraged to forward a Curriculum Vitae to Dr. Shannon at: [email protected].